Designed Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Variants Initiating Apoptosis Exclusively via the DR5 Receptor

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anticancer drug that selectively induces apoptosis in a variety of cancer cells by interacting with death receptors DR4 and DR5. TRAIL can also bind to decoy receptors (DcR1, DcR2, and osteoprotegerin receptor) that canno...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-06, Vol.103 (23), p.8634-8639
Main Authors: van der Sloot, Almer M., Tur, Vicente, Szegezdi, Eva, Mullally, Margaret M., Cool, Robbert H., Samali, Afshin, Serrano, Luis, Quax, Wim J.
Format: Article
Language:English
Subjects:
Amino acids
Antibodies
Apoptosis
Apoptosis Regulatory Proteins - metabolism
Biochemistry
Biological Sciences
Cancer
Cell death
Cell Line, Tumor
Cell lines
Computational Biology
Gangrene
Human umbilical vein endothelial cells
Humans
Ligands
Membrane Glycoproteins - metabolism
Models, Molecular
Myeloid cells
Ovarian cancer
Protein Binding
Proteins
Receptors
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor - metabolism
Surface Plasmon Resonance
TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor-alpha - metabolism
Tumors
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Summary:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anticancer drug that selectively induces apoptosis in a variety of cancer cells by interacting with death receptors DR4 and DR5. TRAIL can also bind to decoy receptors (DcR1, DcR2, and osteoprotegerin receptor) that cannot induce apoptosis. The occurrence of DR5-responsive tumor cells indicates that a DR5 receptor-specific TRAIL variant will permit tumor-selective therapies. By using the automatic design algorithm FOLD-X, we successfully generated DR5-selective TRAIL variants. These variants do not induce apoptosis in DR4-responsive cell lines but show a large increase in biological activity in DR5-responsive cancer cell lines. Even wild-type TRAIL-insensitive ovarian cancer cell lines could be brought into apoptosis. In addition, our results demonstrate that there is no requirement for antibody-mediated cross-linking or membrane-bound TRAIL to induce apoptosis through DR5.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0510187103